Resolution of prostaglandin intermediates by means of oxazolidines

ABSTRACT

Process for resolving a racemic mixture of an oxo-type prostaglandin intermediate by (a) converting the oxo compound by reaction with an optically active ephedrine to a mixture of oxazolidine diastereomers, (b) separating at least one oxazolidine diastereomer from said mixture, (c) hydrolyzing said oxazolidine to free the optically active oxo compound, and (d) recovering said optically active oxo compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of then copending application Ser. No. 181,246 filedSept. 16, 1971, now issued as U.S. Pat. No. 3,711,515, which was acontinuation-in-part of then copending application Ser. No. 93,483,filed Nov. 27, 1970, and since abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a process for preparing intermediates usefulin the preparation of prostaglandins, (hereinafter identified as "PGE₂," "PGF₂.sub.α, " etc.) and to a process for preparing racemic andoptically active PGE₃ and PGF₃.sub.α, their enantiomorphs and their15-epimers.

Previously, the preparation of a racemic bicyclic lactone diol of theformula ##SPC1##

Was reported by E. J. Corey et al., J, Am. Chem. Soc. 91, 5675 (1969),and later disclosed in an optically active form by E. J. Corey et al.,J. Am. Chem. Soc. 92, 397 (1970). Conversion of this intermediate toPGE₂ and PGF₂.sub.α, either in dl-form or optically active form, wasdisclosed in those publications.

It is well known that the prostaglandin structures have several centersof asymmetry and therefore exist as stereoisomers (see Nugteren et al.,Nature 212, 38-39 (1966); Bergstrom et al., Pharmacol. Rev. 20, 1(1968)). Each formula for PGE₂, PGF₂.sub.α, PGE₃, and PGF₃.sub.α hereinrepresents a molecule of the optically active naturally-occuring from ofthe prostaglandin.

PGE₂ has the following structure: ##SPC2##

PGF₂.sub.α has the following structure: ##SPC3##

PGE₃ has the following structure: ##SPC4##

PGF₃.sub.α has the following structure: ##SPC5##

See also FIGS. XVI, XXII, XXIV, and XXVI herein, which are identical tothe above formulas when ˜ represents attachment of hydroxyl in the α (S)configuration. The mirror image of each formula represents a molecule ofthe enantiomorphic form of that prostaglandin. Thus, for example,"ent-PGE₃ " refers to the enantiomorph of PGE₃. The racemic or "dl" formof the prostaglandin consists of equal numbers of two types ofmolecules, e.g., a natural-configuration prostaglandin and itsenantiomorph. If one of the optically active isomers has dextro opticalrotatory power, the other has an equal degree of laevo optical rotatorypower. A racemic mixture of equal quantities of d- and l- isomersexhibits no optical rotation. The reaction of the components of aracemic mixture with an optically-active substance results in theformation of diastereomers having different physical properties, e.g.degree of solubility in a solvent. Another term used herein is"15--epimer." When referred to one of the above prostaglandins, itidentifies a molecule having the opposite configuration at the C--15atom. Thus, "15β--PGE₃ refers to the product having the β (R)configuration at carbon 15 as compared with the α (S) configuration forPGE₃.

PGE₂, PGF₂.sub.α, PGF₂.sub.β, and PGA₂, and their esters, acylates, andpharmocologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom et al.,Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few ofthose biological responses are systemic arterial blood pressure loweringin the case of the PGE₂, PGF₂.sub.β, and PGA₂ compounds as measured, forexample, in anesthetized (pentobarbital sodium) pentolinium-treated ratswith indwelling aortic and right heart cannulas; pressor activity,similarly measured, for the PGF₂.sub.α compounds; stimulation of smoothmuscle as shown, for example, by tests on strips of guinea pig ileum,rabbit duodenum, or gerbil colon; potentiation of other smooth musclestimulants, antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE₂ and PGA₂compounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; decrease ofblood platelet adhesiveness as shown by platelet-to-glass adhesiveness,and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE₂ compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE₂ compounds, areuseful in mammls, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE₂ and PGA₂ compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 μg. to about 500 μg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg. per kg. of bodyweight per day are used, the exact dose depending on the age, weight,and condition of the patient or animal, and on the frequency and routeof administration.

The PGE₂, PGF₂.sub.α, and PGF₂.sub.β compound are useful whenever it isdesired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, and to remove or prevent the formation ofthrombi in mammals, including man, rabbits, and rats. For example, thesecompounds are useful in the treatment and prevention of myocardialinfarcts, to treat and prevent post-operative thrombosis, to promotepatency of vascular grafts following surgery, and to treat conditionssuch as atherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE₂, PGF₂.sub.α, and PGF₂.sub.β compounds are especially useful asadditives to blood, blood products, blood substitutes, and other fluidswhich are used in artificial extracorporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to theoriginal body, detached and being preserved or prepared for transplant,or attached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE₂ compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore PGE₂, for example, is useful in place of or in combinationwith less than usual amounts of these known smooth muscle stimulators,for example, to relieve the symptoms of paralytic ileus, or to controlor prevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE₂ compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 μg. per. kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE₂, PGF₂.sub.β, and PGA₂ compounds are useful as hypotensiveagents to reduce blood pressure in mammals including man. For thispurpose, the compounds are administered by intravenous infusion at therate of about 0.01 to about 50 μg. per kg. of body weight per minute, orin single or multiple doses of about 25 to 500 μg. per kg. of bodyweight total per day.

The PGE₂, PGF₂.sub.α, and PGF₂.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the compound is infused intravenously at a dose 0.01 to 50 μg.per. kg. of body weight per minute until or near the termination of thesecond stage of labor, i.e., expulsion of the fetus. These compounds areespecially useful when the female is one or more weeks post-mature andnatural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started.

The PGE₂, PGF₂.sub.α, and PGF₂.sub.β compounds are useful forcontrolling the reproductive cycle in ovulating female mammals,including humans and other animals. For that purpose, PGF₂.sub.α, forexample, is administered systemically at a dose level in the rangedl-Tricyclic 20 mg. per kg. of body weight, advantageously during a spanof time starting approximately at the time of ovulation and endingapproximately at ˜time of menses or just prior to menses. Additionally,expulsion of an embryo or a fetus is accomplished by similaradministration of the compound during the first third of the normalmammalian gestation period. Because the PGE₂ compounds are potentantagonists of epinephrine-induced mobilization of free fatty acids,they are useful in experimental medicine for both in vitro and in vivostudies in mammals, including man, rabbits, and rats, intended to leadto the understanding, prevention, symptom alleviation, and cure ofdiseases involving abnormal lipid mobilization and high free fatty acidlevels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The PGE₂ compounds promote and accelerate the growth of epidermal cellsand keratin in animals, including humans, and other animals. For thatreason, these compounds are useful to promote and accelerate healing ofskin which has been damaged, for example, by burns, wounds, andabrasions, and after surgery. These compounds are also useful to promoteand accelerate adherence and growth of skin autografts, especiallysmall, deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 5to 1000 μg./ml. of the PGE₂ compound. Especially for topical use, theseprostaglandins are useful in combination with antibiotics, for example,gentamycin, neomycin, polymyxin B , bacitracin, spectinomycin, andoxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example, hydrocortisone, prednisolone,methylprednisolone, and fluprednisolone, each of those being used in thecombination at the usual concentration suitable for its use alone.

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide processes for theproduction of compounds useful in the preparation of prostaglandinscommercially in substantial amount and at reasonable cost. It is afurther purpose to provide processes for preparing certain intermediatesin optically active forms. It is still a further purpose to provide aprocess for preparing racemic and optically active PGE₃, PGF₃.sub.α,PGF₃.sub.β, and PGA₃, their enantiomorphs, and their 15-epimers.

The presently described processes and intermediates are useful forpreparing PGE₂, PGF₂.sub.α, and PGA₂ and their racemic forms, which areknown to be useful for the above-described pharmacological purposes. Theprocesses and intermediates disclosed herein are also useful forpreparing enantiomorphic PGE₂, PGF₂.sub.α,PGF₂.sub.β and PGA₂, and PGE₃,PGF₃.sub.α, PGF₃.sub.β, and PGA₃ , their enantiomorphs, and their15β-epimers, each one of which is useful for the above-describedpharmacological purposes, and is used for those purposes in the samemanner as described above. These novel compounds are substantially morespecific with regard to potency in causing prostaglandin-like biologicalresponses. Therefore, each of these novel prostaglandin-type compoundsis surprisingly and unexpectedly more useful than one of thecorresponding above-mentioned known prostaglandins for at least one ofthe pharmacological purposes indicated above for the latter, because ithas a different and narrower spectrum of biological potency than theknown prostaglandins, and therefore is more specific in its activity andcauses smaller and fewer undesired side effects than when the knownprostaglandin is used for the same purpose.

Thus, there is provided a process for preparing an optically activetricyclic lactone glycol of the formula ##SPC6##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein Y is 1-pentyl or 1-pent-2-ynyl, and ˜indicates attachment of the moiety to the cyclopropane ring in exo orendo configuration and to the side chain in alpha or beta configuration,which comprises the steps of:

a. converting optically active or racemic bicyclo-[3.1.0]hex-2-ene-6-carboxaldehyde to an optically active acetal of the formula ##SPC7##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein R₁ and R₂ are alkyl of one to 4 carbonatoms, inclusive, or, when taken together, ##EQU1## wherein R₃, R₄, R₅,R₆, R₇, and R₈ are hydrogen, alkyl of one to 4 carbon atoms, inclusive,or phenyl, with the proviso that not more than one of the R's is phenyland the total number of carbon atoms is from 2 to 10, inclusive; x iszero or one, and ˜ is as defined above;

b. Transforming said optically active or racemic acetal to an opticallyactive tricyclic mono or dihaloketone of the formula ##SPC8##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein R₁, R₂, and ˜ are as defined above,and wherein R₁₀ is bromo or chloro, and R₁₁ is hydrogen, bromo, orchloro;

c. Transforming said optically active or racemic tricyclic mono ordihaloketone to an optically active tricyclic ketone of the formula##SPC9##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein R₁, R₂, and ˜ are as defined above;

d. oxidizing said optically active or racemic tricyclic ketone to anoptically active tricyclic lactone acetal of the formula ##SPC10##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein R₁, R₂, and ˜ are as defined above;

e. hydrolyzing said optically active or racemic tricyclic lactone to anoptically active tricyclic lactone aldehyde of the formula ##SPC11##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein ˜ is as defined above;

f. converting said optically active or racemic tricyclic lactonealdehyde to an optically active tricyclic lactone alkene or alkenyne ofthe formula ##SPC12##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein Y and ≠ are as defined above; and

g. hydroxylating said optically active or racemic tricyclic lactonealkene or alkenyne to form said optically active or racemic tricycliclactone glycol.

Reference to Chart A, herein, will make clear the transformation frombicyclic akdehyde l to tricyclic lactone glycol VIII by steps a-g,inclusive. Formulas l-X, inclusive, hereinafter referred to, aredepicted in Chart A, wherein R₁ and R₂ are alkyl of one to 4 carbonatoms, inclusive, or, when taken together, ##EQU2## wherein R₃, R₄, R₅,R₆, R₇, and R₈ are hydrogen , alkyl of one to 4 carbon atoms, inclusive,or phenyl, with the proviso that not more than one of the R's is phenyland the total number of carbon atoms is from 2 to 10, inclusive; and xis zero or one; wherein R₉ is alkyl of one to 5 carbon atoms, inclusive,R₁₀ is bromo or chloro, and R₁₁ is hydrogen, bromo, or chloro; wherein Yis 1-pentyl or 1-pent-2-ynyl; wherein W is 1-pentyl, cis 1-pent-2-entyl,or 1-pent-2-ynyl; and wherein ˜ indicates attachment of the moiety tothe cyclopropane ring in exo or endo configuration, or attachment of thehydroxyl to the side chain in alpha or beta configuration.

In the formulas herein, the broken line attachments to a ring representsubstituents in alpha configuration, i.e., below the plane of the paper.The wavy line ˜ indicates attachment of a group to a cyclopentane orlactone ring in alpha or beta configuration, or it indicates attachmentto a cyclopropane ring in exo or endo configuration, or it indicatesattachment to the C-15 carbon of the prostamoic acid skeleton in α (S)or β (R) configuration. The formula of each intermediate as drawn hereinis intended to represent the particular optical isomer which istransformed by the processes herein to an optically active prostaglandinhaving the natural configuration of prostaglandins obtained frommammalian tissues. The mirror image of each formula then represents amolecule of the enantiomorphic form of that intermediate. The expression"racemic compound" refers to a mixture of the optically active isomerwhich yields the natural configuration prostaglandin and the poticallyactive isomer which is its enantiomorph.

CHART A ##SPC13##

The bicyclic aldehyde of Formula I in Chart A exists in a number ofisomeric forms. With respect to the attachment of the --CHO group, itexists in two isomeric forms, exo and endo. Also, with respect to theposition of the cyclopentene double bond relative to the --CHO group,each of the exo and endo forms exists in two optically active (d- or 1-)forms, making in all four isomers. Each of those isomers separately ormixtures thereof undergo the reactions herein for producingprostaglandin intermediates and products. For racemic products theunresolved isomers are used. For the optically active prostaglandins,the aldehyde or subsequent intermediate isomers are resolved by my newprocess disclosed herein, and are used for preparing the opticallyactive products. The preparation of the exo and endo aldehydes isdiscussed below under "Preparations."

In carrying out step a, bicyclic aldehyde I is transformed to acetal IIby methods known in the art. Thus, aldehyde I is reacted with either analcohol of one to 4 carbon atoms, e.g., methanol, ethanol, propanol, orbutanol in their isomeric forms, or mixture of such alcohols, or,preferably, a glycol having the formula VI: ##EQU3## wherein R₃, R₄, R₅,R₆, R₇, and R₈ are hydrogen, alkyl of one to 4 carbon atoms, inclusive,or phenyl, with the proviso that not more than one of the R's is phenyland the total number of carbon atoms is from 2 to 10, inclusive; and xis zero or one. Examples of suitable glycols are ethylene glycol,1,2-propanediol, 1,2-hexanediol, 1,3-butanediol, 2,3-pentanediol,2,4-hexanediol, 3,4-octanediol, 3,5-nonanediol,2,2-dimethyl-1,3-propanediol, 3,3-dimethyl-2,4-heptanediol,4-ethyl-4-methyl-3,5-heptanediol, phenyl-1,2-ethanediol, and1-phenyl-1,2-propanediol.

The step-a reaction is carried out under a variety of conditions usingprocedures generally known in the art. Thus, the reactants are dissolvedin benzene and the mixture heated to remove the water formedazeotropically. To accelerate the reaction, there may be added an acidcatalyst such as p-toluenesulfonic acid, trichloroacetic acid, zincchloride, and the like. Alternatively, the reactants, together with theacid catalyst and a water scavenger such as trimethyl orthoformate arewarmed to 40°-100°C. in an inert solvent such as benzene, toluene,chloroform, or carbon tetrachloride. The ratio of the aldehyde to theglycol is preferably between 1:1 and 1:4.

In transforming acetal II to ketone IV, reactions known in the art foranalogous compounds are employed. In carrying out step b, acetal II isreacted with a ketene R₁₀ R₁₁ C=C=O, for example HBrC=C=O, HClC=C=O, Br₂C=C=O, or Cl₂ C=C=O. For convenience, ketene Cl₂ C=C=O is preferred. Itis preferably generated in situ by the reaction of a 0.5-to-2.0-foldexcess of dichloroacetyl chloride in the presence of a tertiary amine,e.g., triethylamine, tributylamine, pyridine, or1,4-diazabicyclo[2.2.2]octane, in a solvent such as n-hexane,cyclohexane, or mixture of isomeric hexanes (Skellysolve B ) at atemperature of from 0° to 70 ° C. (See, for example, Corey et al.,Tetrahedron Letters No. 4, pp. 307-310, 1970). Alternatively, the keteneCl₂ C=C=O is generated by adding a trichloroacyl halide to zinc dustsuspended in the reaction vessel, omitting the tertiary amine.

In carrying out step c, mono- or dihaloketone III is reduced with a2-to-5-fold excess of zinc dust over the stoichiometric ratio of Zn:2Clin methanol, ethanol, ethylene, glycol, and the like, in the presence ofacetic acid, ammonium chloride, sodium bicarbonate or sodium dihydrogenphosphate. Alternatively, the reaction is carried out with aluminumamalgam in a water-containing solvent such as methanol-diethylether-water, tetrahydrofuran-water, or dioxane-water, at about 0°-50° C.

In carrying out step d, tricyclic acetal ketone IV is converted to alactone by methods known in the art, for example by reaction withhydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoicacid, and the like, in the presence of a base such as alkali hydroxide,bicarbonate, or orthophosphate, using a preferred molar ratio ofoxidizer to ketone of 1:1.

In carrying out step e, lactone acetal V is converted to aldehyde VI byacid hydrolysis, known in the art, using dilute mineral acids, acetic orformic acids, and the like. Solvents such as acetone, dioxane, andtetrahydrofuran are used.

In carrying out step f, aldehyde VI is transformed to the Formula-VIIalkene or alkenyne, for example by means of an ylid as in the Wittigreaction. A 1-hexyl halide or 1-hex-3-ynyl halide, preferably thebromide, is used to prepare the Wittig reagent, e.g.hexyltriphenylphosphonium bromide or (hex-3-ynyl)triphenylphosphoniumbromide.

In carrying out step g, the Formula-VII alkene or alkenyne ishydroxylated to glycol VIII by procedures known in the art. See SouthAfrican Pat. No. 69/4809 issued July 3, 1970. In the hydroxylation ofthe respective endo or exo alkenes, various isomeric glycols areobtained depending on such factors as whether the --CH=CH--moiety in VIIis cis or trans, and whether a cis or a trans hydroxylation reagent isused. Thus, endo-cis olefin gives a mixture of two isomeric erythroglycols of Formula VIII with a cis hydroxylation agent, e.g., osmiumtetroxide. Similarly, the endotrans olefin gives a similar mixture ofthe same two erythro glycols with a trans hydroxylation agent, e.g.,hydrogen peroxide. The endo-cis olefins and the endo-trans olefins givesimilar mixtures of two threo glycol isomers with trans and cishydroxylation reagents, respectively. These various glycol mixtures areseparated into individual isomers by silica gel chromatography. However,this separation is usually not necessary, since each isomeric erythroglycol and each isomeric threo glycol is useful as an intermediateaccording to this invention and the processes outlined in Chart A toproduce intermediate products of Formula X and then, according to ChartsC through F hereinafter to produce the other final products of thisinvention. Thus, the various isomeric glycol mixtures encompassed byFormula VIII produced from the various isomeric olefins encompassed byFormula VII are all useful for these same purposes. CHART B ##SPC14##CHART C ##SPC15## CHART D ##SPC16##

CHART E ##SPC17## CHART F ##SPC18##

There is further provided by this invention a process for preparing anoptically active bicyclic lactone diol of the formula ##SPC19##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein W is 1-pentyl, cis 1-pent-2-enyl, or1-pent-2-ynyl, and ˜ indicates attachment of the hydroxyl to the sidechain in alpha or beta configuration, which comprises the steps of:

a. replacing the glycol hydrogens of an optically active tricycliclactone glycol of the formula ##SPC20##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, by an alkanesulfonyl group, R₉ O₂ S--, whereinR₉ is alkyl of one to 5 carbon atoms, inclusive, and ˜ indicatesattachment of the moiety to the cyclopropane ring in exo or endoconfiguration and to the side chain in alpha or beta configuration; and

b. mixing the compound formed in step a with water at a temperature inthe range of 0° to 60 ° C. to form said optically active or racemicbicyclic lactone diol.

Glycol VIII is transformed by steps h and i into diol X as shown inChart A. The procedures for forming the Formula-IX bis(alkanesulfonicacid) ester by replacing the glycol hydrogen by an alkanesulfonyl group,and subsequently hydrolyzing that ester to diol X are known in the art(see South African patent cited immediately above).

In Chart A, there are differences in the terminal groups on the sidechains of Formulas VII and VIII. In Formula VII, Y is limited to1-pentyl or 1-pent-2-ynyl whereas in Formula VIII, W includes 1-pentyl,cis 1-pent-2-enyl, or 1-pent-2-ynyl. The compounds of Formula VIII, IX,or X wherein W is cis 1-pent-2-enyl are obtained by reducing the--C.tbd.C-- moiety of the 1-pent-2-ynyl group to cis --CH=CH-- before orafter any of the steps h or i, i.e., at any stage after thehydroxylation of the --CH=CH-- moiety in step g. For that purpose, thereare used any of the known reducing agents which reduce an acetyleniclinkage to a cis-ethylenic linkage. Especially preferred for thatpurpose are diimide or hydrogen and a catalyst, for example, palladium(5%) on barium sulfate, especially in the presence of pyridine. SeeFieser et al., "Reagents for Organic Synthesis," pp. 566-567, John Wiley& Sons, Inc., New York, N.Y. (1967).

There is further provided a process for preparing an optically activebicyclic lactone diol of the formula ##SPC21##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein W is 1-pentyl, cis 1-pent-2-enyl, or1-pent-2-ynyl, and ˜ indicates attachment of the hydroxyl to the sidechain in alpha or beta configuration, which comprises starting with anoptically active tricyclic lactone alkene or alkenyne of the formula##SPC22##

or the mirror image thereof, or a racemic compound of that formula andthe mirror image thereof, wherein Y is 1-pentyl or 1-pent-2-ynyl and ˜indicates attachment of the moiety to the cyclopropane ring in exo orendo configuration, and subjecting said alkene or alkenyne successivelyto the following reactions:

a. oxidation of the --CH=CH-- moiety to an epoxy ring,

b. hydrolysis of the resulting epoxide to a mixture of said bicycliclactone diol and a tricyclic lactone glycol,

c. formolysis of said mixture to form a diformate of said bicycliclactone diol, and

d. hydrolysis of said diformate to said bicyclic lactone diol,

with the proviso that, when W is cis 1 -pent-2-enyl, the --C=C-- moietyis reduced to cis --CH=CH-- before or after any of the steps b to d.

Reference to Chart B, herein, will make clear the transformation fromthe Formula-VII lactone alkene or alkenyne to diols X.sub.α and X.sub.β.Formulas VII, X.sub.α, X.sub.β, XXXVIII, XXXIX, and XL, hereinafterreferred to, are depicted in Chart B, wherein E and M are both hydrogenor wherein one of E and M is hydrogen and the other is formyl, wherein Yis 1-pentyl or 1-pent-2-ynyl, wherein ˜ indicates attachment of themoiety to the cyclopropane ring in exo or endo configuration, orattachment of OE and OM in threo or erythro configuration, or attachmentto the side chain in alpha or beta configuration, and wherein ##EQU4##indicates attachment of the epoxide oxygen to the side chain in alpha orbeta configuration.

The Formula-VII alkene or alkenyne, prepared by steps a-f of Chart A, istransformed to epoxide XXVIII by mixing reactant VII with a peroxycompound which is hydrogen peroxide or, preferably, an organicpercarboxylic acid. Examples of useful organic percarboxylic acids forthis purpose are performic acid, peracetic acid, perlauric acid,percamphoric acid, perbenzoic acid, m-chloroperbenzoic acid, and thelike. Peracetic acid is especially preferred.

The peroxidation is advantageously carried out by mixing the reactantVII with about one equivalent of the per acid or hydrogen peroxide,advantageously in a diluent, for example, chloroform. The reactionusually proceeds rapidly, and the Formula-XXXVIII epoxide is isolated byconventional methods, for example, evaporation of the reaction diluentand removal of the acid corresponding to the per acid if one is used. Itis usually unnecessary to purify the oxide before using it in the nextstep.

Two procedures are available for transforming epoxide XXXVIII to dioldiformate XL. In one, the epoxide is hydrolyzed to a mixture of glycolXXXIX, wherein E and M are hydrogen, and diol X.sub.α₊.sub.β. For thispurpose, a solution of dilute formic acid in an inert miscible solventsuch as acetone, dimethyl sulfoxide, ethyl acetate, or tetrahydrofuranis used. Reaction temperatures of -20° C. to 100° C. may be employed,although about 25° C. is preferred. At lower temperatures, the desiredmixture is produced inconveniently slowly. At higher temperatures,undesired side reactions reduce the yield of the desired mixture.Thereafter, the glycol-diol mixture is contacted with formic acid,preferably substantially 100% formic acid, at about 25° C. to form thediol formate. By "substantially 100% formic acid" is meant a purity ofat least 99.5%.

In the other procedure, epoxide XXXVIII is subjected to formolysisdirectly. Preferably substantially 100% formic acid is used, at about25° C. An inert solvent such as dichloromethane, benzene, or diethylether may be employed.

In either procedure, glycol monoformate XXXIX, wherein one of E and M ishydrogen and the other is formyl, is often present as an intermediate.It is ordinarily not isolated, but is converted to diol diformate XL insubstantially 100% formic acid.

The diol diformate XL is obtained as a mixture of isomers in which theformyl group on the side chain are in the alpha and beta configurations.The mixture is converted directly to the diols X.sub.α and X.sub.βwithout separation. For this purpose, the diol diformates are contactedwith a weak base such as an alkali metal carbonate, bicarbonate, orphosphate, preferably sodium or potassium bicarbonate, in a loweralkanol, for example methanol or ethanol. For this base hydrolysis, atemperature range of 10° C. to 50° C. is operable, preferably about 25°C. The product is a mixture containing the diols X.sub.α and X.sub.β,wherein the hydroxyl on the side chain is in the alpha and betaconfiguration. Separation of the alpha and beta diols is done by knownprocedures. Especially useful here is chromatography, for example onsilica gel or alumina.

In Chart B, there are differences in the terminal groups on the sidechains of Formulas VII, XXXVIII, XXXIX, XL, X.sub.α and X.sub.β. InFormula VII, Y is limited to 1-pentyl or 1-pent-2-ynyl whereas in theother formulas W includes 1-pentyl, cis 1-pent-2-enyl, or 1-pent-2-ynyl.Similarly to Chart A above, the compounds wherein W is cis 1-pent-2-enylare obtained by reducing the --C.tbd.C-- moiety to cis --CH=CH-- bymethods known in the art at any stage after the epoxidation of the--CH=CH-- moiety of compound VII.

The formation of PGE₂ or PGF₂.sub.α from the Formula-X.sub.α lactonediol intermediate is done by the steps shown in Charts C and E known inthe art. See E. J. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969). TheFormula-XI compound is within the scope of the Formula-X diol when W isn-C₅ H₁₁. The formation of PGF₂.sub.β by carbonyl reduction of PGE₂ isknown in the art. For this reduction, use is made of any of the knownketonic carbonyl reducing agents which do not reduce ester or acidgroups or carbon-carbon double bonds when the latter is undesirable.Examples of those are the metal borohydrides, especially sodium,potassium, and zinc borohydrides, lithium (tri-tert-butoxy) aluminumhydride, metal trialkoxy borohydrides, e.g., sodiumtrimethoxyborohydride, lithium borohydride, diisobutyl aluminum hydride,and when carbon-carbon double bond, especially cis, reduction is not aproblem, the boranes, e.g., disiamylborane. As is known, this methodgives a mixture of PGF₂.sub.α and PGF₂.sub.β, which are readilyseparated by chromotography. The formation of PGA₂ by acidic dehydrationof PGE₂ is known in the art. See, for example, Pike et al., Proc. NobelSymposium 11, Stockholm (1966), Interscience Publishers, New York, p.162 (1967), and British Specification 1,097,533. Alkanoic acids of 2 to6 carbon atoms, inclusive, especially acetic acid, are preferred acidsfor this acidic dehydration. Dilute aqueous solutions of mineral acids,e.g., hydrochloric acid, especially in the presence of a solubilizingdiluent, e.g., tetrahydrofuran, are also useful as reagents for thisacidic dehydration.

With regard to Formulas II to XXXIV, examples of alkyl of one to 4carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomericforms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive,are those given above, and pentyl, hexyl, heptyl, octyl, and isomericforms thereof. In Formulas XI-XVI and elsewhere, "n-C₅ H₁₁ " representsthe normal-pentyl group, and "THP" represents the tetrahydropyranylgroup.

There is further provided a process for preparing PGE₃, d1-PGE₃, ortheir 15-epimers, which comprises starting with an optically activeglycol of the formula ##SPC23##

or a racemic compound of that formula and the mirror image thereof,wherein ˜ indicates attachment of the moiety to the cyclopropane ring inexo or endo configuration and to the side chain in alpha or betaconfiguration, and subjecting said glycol successively to the followingreactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R₉ O₂S--, wherein R₉ is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0° to 60° C. toform a bicyclic lactone diol of S and R configuration;

c. separation of said diols of S and R configuration;

d. transformation to a bis(tetrahydropyranyl) ether;

e. reduction of the lactone oxo group to a hydroxy group;

f. Wittig alkylation with a compound of the formula Hal--(CH₂)₄ --COOHwherein Hal is bromo or chloro;

g. oxidation of the 9-hydroxy to oxo; and

h. transformation of the two tetrahydropyranyloxy groups to hydroxygroups;

with the proviso that, before or after any of the steps a to h, the--C.tbd.C-- moiety is reduced to cis --CH=CH--.

Reference to Charts A and D, herein, will make clear the transformationfrom bicyclic aldehyde I to PGE₃, ent-PGE₃, dl-PGE₃, or their15-epimers. In Chart D, Z is cis 1-pent-2-enyl or 1-pent-2-ynyl, and ˜and THP are as defined above. A key intermediate for this sequence isthe racemic or optically active lactone aldehyde VI. The Formula-VIcompound is prepared from racemic bicyclic aldehyde I by steps a-e ofChart A and thereafter resolved in an optically active form by themethod disclosed hereinafter via the oxazolidine of Example 15.Optionally, the Formula-I aldehyde is resolved as disclosed hereinafterin Example 13, and thereafter converted to the optically activeFormula-VI compound.

In carrying out step f of Chart A, the Wittig reaction is employed,using a 1-hex-2-ynyl chloride, bromide, or iodide, preferably bromide,to prepare the necessary Wittig reagent by processes known in the art.

In carrying out steps g through i of Chart A, the procedures forhydroxylating the Formula-VII alkenyne wherein Y is 1-pent-2-ynyl,forming the Formula-IX bis-(alkanesulfonic acid) ester, and hydrolyzingthat ester to the Formula-X lactone diol are generally known in the art.See South African Pat. 69/4809 issued July 3, 1970. The Formula-Xlactone diol, which contains both α and β epimers as produced, yieldsthe final product as a mixture of PGE₃ and its 15-epimer. It ispreferable that the diol α and β epimers be separated rather than thefinal product epimers. Silica gel chromatography is employed for thispurpose. The Formula-X β-epimer then leads to the dl-15β-PGE₃.

In converting glycol VIII, wherein W is 1-pent-2-ynyl, to theFormula-XXII product, the --C.tbd.C-- moiety is reduced to cis --CH=CH--at any stage. Thus, glycol VIII is optionally reduced before replacingthe glycol hydrogens with an alkanesulfonyl group; or any of theFormula-IX, -X, -XVIII, -XIX, -XX, or -XXI intermediates is optionallyreduced. Reducing reagents, catalysts and conditions are used which donot substantially reduce --CH=CH--. A suitable method is to hydrogenateover a Lindlar catalyst, i.e. 5% palladium-on-barium sulfate catalyst,in the presence of quinoline. Methanol or like inert solvent or diluentis used and the pressure is low, advantageously slightly aboveatmospheric and ordinarily not above about two atmospheres. Theresulting products are isolated by silica gel chromatography.

The formation of PGE₃ from the Formula-XVII diol intermediate by thesteps of Chart D, other than the reduction step above-described,generally follows procedures known in th art and discussed above underthe formation of PGE₂.

There is further provided a process for preparing PGF₃.sub.α,dl-PGF₃.sub.α, or their 15-epimers, in which glycol VIII, wherein W is1-pent-2-ynyl, is transformed to diol XVII, wherein Z is cis1-pent-2-enyl or 1-pent-2-ynyl, and thence to the Formula-XXVI products,as depicted by the steps of Chart F. Accordingly, diol XVII is reducedto lactol XXV which is then alkylated by a Wittig reaction. As in theprocess for PGE₃, the --C.tbd.C-- moiety is reduced to cis --CH=CH-- atany stage between the glycol and the end-product. As in the process forPGE₃, the optical isomers of the intermediates yield the correspondingPGF₃.sub.α or ent-PGF₃.sub.α ; the racemic intermediates yield racemicPGF₃.sub.α ; the optically active α- and β-configuration intermediatesyield the corresponding PGF₃.sub.α, ent-PGF₃.sub.α, or their 15-epimers.

The formation of racemic and optically active PGF₃.sub.β from racemicand optically active PGE₃ generally follows procedures known in the art,e.g., by carbonyl reduction with borohydride, discussed above under theformation of PGF₂.sub.β. The formation of racemic and optically activePGA₃ from racemic and optically active PGE₃ likewise follows proceduresknown in the art, e.g., by acidic dehydration, discussed above under theformation of PGA₂.

There is further provided a process for resolving a racemic mixture ofan oxo compound of the formula ##SPC24##

and of the mirror image thereof, wherein R₁ and R₂ are alkyl of one to 4carbon atoms, inclusive, or, when taken together, ##EQU5## wherein R₃,R₄, R₅, R₆, and R₈ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or phenyl, with the proviso that not more than one of the R'sis phenyl and the total number of carbon atoms is from 2 to 10,inclusive; x is zero or one, and ˜ indicates attachment of the moiety tothe cyclopropane ring in exo or endo configuration, which comprises thesteps of:

a. converting the oxo compound by reaction with an optically activeephedrine to a mixture of oxazolidine diastereomers,

b. separating at least one oxazolidine diastereomer from said mixture,

c. hydrolyzing said oxazolidine to free the optically active oxocompound, and

d. recovering said optically active oxo compound.

In carrying out the resolution of the Formula-I bicyclic aldehyde, thereis prepared an oxazolidine by reaction of the aldehyde with an opticallyactive ephedrine, e.g. d- or l-ephedrine, or d- or l-pseudoephedrine.Approximately equi-molar quantities of the reactants are employed in asolvent such as benzene, isopropyl ether, or dichloromethane. Althoughthe reaction proceeds smoothly over a wide range in temperature, e.g.,10°-80° C., it is preferred that it be done in the range 20° to 30° C.to minimize side reactions. With the Formula-I compound, it occursquickly, within minutes, whereupon the solvent is removed, preferablyunder vacuum. The product consists of the diastereomers of thealdehyde-ephedrine product, i.e. the oxazolidines. At least one of thediastereomers is separated by methods known in the art, includingcrystallization and chromatography. In this instance, crystallization isused as the preferred method. Repeated recrystallization of thethus-obtained solid oxazolidine from a suitable solvent, e.g., isopropylether, yields one of the diastereomers in substantially pure form. Theoxazolidine is then hydrolyzed by procedures known in the art to releasethe aldehyde. However, I have found silica gel wet with watersurprisingly effective, using the silica gel in a column, with thefurther beneficial effect that the column acts as a means of separatingthe ephedrine from the aldehyde. The eluted fractions are thenevaporated to yield the desired resolved Formula-I aldehyde.

The mother liquor from the recrystallized diastereomer contains theoptical isomer having opposite configuration. A preferred method forisolating this second diastereomer, however, is to prepare theoxazolidine of the racemic aldehyde using ephedrine of the oppositeconfiguration to that first employed above, and thereafterrecrystallizing as above. Finally, hydrolysis and recovery yield theresolved Formula-I aldehyde in opposite configuration to that firstobtained above.

I have further found that this method is generally applicable forresolving aldehydes and ketones, and is useful for resolving not onlythe Formula-I aldehyde but also the Formula-VI lactone aldehyde and theFormula-IV acetal ketone.

There is still further provided the new compounds produced by the aboveprocesses, all of which are useful intermediates in these processesdirected toward prostaglandins, viz. bicyclic aldehyde I in itsoptically active forms; acetal II; mono or dihaloketone III, ketone IV;lactone acetal V; lactone aldehyde VI; the Formula-VII lactone hepteneor heptenyne; lactone glycol VIII and monoformate XXXIX of the genericformula ##SPC25##

wherein E and M are both hydrogen, or wherein one of E and M is hydrogenand the other is formyl, and wherein W is 1-pentyl, cis 1-pent-2-enyl,or 1-pent-2-ynyl; the lactone bis(alkanesulfonate) IX of the formula##SPC26##

wherein R₉ is alkyl of one to 5 carbon atoms, inclusive, and W is asdefined above;

epoxide XXXVIII of the formula ##SPC27##

wherein W is as defined above, and wherein ##EQU6## indicates attachmentof the epoxide oxygen to the side chain in α or β configuration;

diformate XL of the formula ##SPC28##

wherein W is as defined above;

lactone diol XII represented by the mirror image of the formula##SPC29##

lactone diol XVII of the formula ##SPC30##

wherein Z is cis 1-pent-2-enyl or 1-pent-2-ynyl; tetrahydropyranyllactone XVIII of the formula ##SPC31##

wherein THP is tetrahydropyranyl and Z is as defined above;

tetrahydropyranyl lactol XIX of the formula ##SPC32##

wherein THP and Z are as defined above;

a Formula-XX compound of the formula ##SPC33##

wherein THP and Z are as defined above; and oxazolidine of bicyclicaldehyde I, ketone IV, or lactone aldehyde VI with an optically activeephedrine. In these compounds indicates attachment to the cyclopropanering in exo or endo configuration and to the side-chain in α (S) or β(R) configuration. There are also provided the enantiomorphs and theracemic mixtures of the above compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is further illustrated by, but not limited to, thefollowing examples.

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

The NMR spectra are recorded on a Varian A-60 spectrophotometer indeuterochloroform solutions with tetramethylsilane as an internalstandard (downfield).

Circular dichroism curves are recorded on a Cary 60 recordingspectropolarimeter.

The collection of chromatographic eluate fractions starts when theeluent front reaches the bottom of the column.

"Brine," herein, refers to an aqueous saturated sodium chloridesolution.

PREPARATION 1 Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde (Formula I:˜ is endo).

To a rapidly stirred suspension of anhydrous sodium carbonate (318 g.)in a solution of bicyclo [2.2.1] hepta-1,5-diene (223.5g.) indichloromethane (1950 ml.) is added 177 ml. of 25.6% peracetic acidcontaining 6 g. of sodium acetate. The addition time is about 45 min.,and the reaction temperature is 20°-26° C. The mixture is stirred for anadditional 2 hrs. The reaction mixture is filtered and the filter cakewashed with dichloromethane. The filtrate and washings are concentratedunder vacuum. About 81 g. of the resulting liquid is stirred with 5 ml.of acetic acid in 200 ml. of dichloromethane for 5.5 hrs., thenconcentrated and distilled. The fraction boiling at 69°-73° C./30 mm.represents the desired Formula-I aldehyde, 73 g. NMR peaks at 5.9 and9.3 (doublet) δ.

The various Formula-I-to-IX intermediates, hereinafter, exist in exo aswell as endo forms. A preferred route to the exo form of the Formula-Ibicyclic aldehyde is by the steps steps shown in Chart G, using methodsknown in the art. See South African Pat. 69/4809 issued July 3, 1970. InFormulas XXVII to XXXVII, the attachment to the cyclopropane ring by astraight line extended downward at an angle to the right indicates theexo configuration. Thus, diazoacetic acid is added to a double bond ofcyclopentadiene to give an exo-endo mixture of the Formula-XXVIIIbicyclo [3.1.0]-hexene substituted at the 6-position with a carboxyl.The exo-endo mixture is treated with a base to isomerize the endo isomerin the mixture to more of the exo isomer. Next the carboxyl group at 6is transformed to an alcohol group and thence to the exo aldehyde of theFormula XXX.

EXAMPLE 1 dl-Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde Acetal ofEthylene Glycol (Formula II: R₁ and R₂ taken together are --CH₂ CH₂ --and ˜ is endo).

Refer to Chart A. A solution of Formula-Iendo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde (216 g., Preparation 1),ethylene glycol (150 g.), and p-toluenesulfonic acid (0.5 g.) in benzene(1 l.) is heated under reflux. The azeotropically distilled water (29ml. after 20 hrs.) is collected in a Dean-Stark trap. The reactionmixture is cooled, treated with sodium carbonate (0.3 g.), and distilledat reduced pressure. The fraction collected at 55°-60° C./3-4 mm. ispartitioned between ether and water. The ether layer is extracted withwater, dried over anhydrous magnesium sulfate, and concentrated to theFormula-II bicyclic acetal, a light tan oil (70 g.); NMR peaks at 1.1,1.6-2.9, 3.5-4.2, 4.42, and 5.3-6.0 δ.

CHART G ##SPC34##

Following the procedures of Example 1 but using the exo Formula-I (XXX)compound, there is obtained the corresponding exo Formula-II acetal.

Following the procedures of Example 1 but using either the endo or exoform of the Formula-I aldehyde and substituting for the ethylene glycolone of the following glycols: 1,2-propanediol, 1,2 -hexanediol,1,3butanediol, 2,3-pentanediol, 2,4-hexanediol, 3,4-octanediol,3,5-nonanediol, 2,2-dimethyl-1,3-propanediol,3,3-dimethyl-2,4-heptanediol, 4-ethyl-4-methyl-3,5-heptanediol,phenyl-1,2-ethanediol and 1-phenyl-1,2-propanediol, there are obtainedthe corrresponding Formula-II acetals.

Following the procedures of Example 1 but using either the endo or exoform of the Formula-I aldehyde and substituting for the ethylene glycolone of the following alcohols: methanol, ethanol, 1-propanol, or1-butanol, there are obtained the corresponding Formula-II acetals.

EXAMPLE 2 dl-Tricyclic Dichloroketone (Formula III: R₁ and R₂ takentogether are --CH₂ CH₂ -- and ˜ is endo).

Refer to Chart A. A solution of the Formula-II bicyclic acetal ofExample 1 (56 g.) and triethylamine (80 g.) in 300 ml. of isomerichexanes (Skellysolve B) is heated at reflux, with stirring, and treateddropwise with dichloroacetyl chloride (100 g.) in Skellysolve B over a3-hour period. The mixture is cooled and filtered to remove solids. Thefiltrate and combined Skellysolve B washes of the filtered solid iswashed with water, 5% aqueous sodium bicarbonate, and brine, dried overanhydrous sodium sulfate and concentrated to the title compound, a darkbrown oil (91 g.). An additional quantity (13 g.) is recovered from thefilter cake and aqueous washes. Alternatively, the triethylamine isadded to a solution of the bicyclic acetal and the dichloroacetylchloride, or the triethylamine and the dichloroacetyl are addedseparately but simultaneously to a solution of the bicyclic acetal inSkellysolve B.

Following the procedures of Example 2 but using the exo Formula-IIcompound, there is obtained the corresponding exo Formula-III tricyclicdichloroketone.

Following the procedures of Example 2, but using the Formula-IIcompounds disclosed following Example 1, there are obtained thecorresponding Formula-III compounds.

EXAMPLE 3 dl-Tricyclic Ketone (Formula IV: R₁ and R₂ are methyl and ˜ isendo).

A solution of the Formula-III dichloroketone of Example 2 (104 g.) indry methanol (1 l.) is treated with ammonium chloride (100 g.) and smallportions of zinc dust. The temperature is allowed to rise to 60° C.After 200 g. of zinc have been added, the mixture is heated under refluxfor an additional 80 min. The mixture is cooled, the solids filteredoff, and the filtrate concentrated. The residue is treated withdichloromethane and 5% aqueous sodium bicarbonate and the mixture isfiltered. The dichloromethane layer is washed with 5% aqueous sodiumbicarbonate and water, dried, and concentrated to the title compound, adark brown oil (56 g.); infra-red absorption at 1760 cm⁻ ¹.

Following the procedures of Example 3 but using the exo Formula-IIIcompound, there is obtained the corresponding exo Formula-IV tricyclicketone.

Following the procedures of Example 3 but using the Formula-IIIcompounds disclosed following Example 2, there are obtained thecorresponding Formula-IV compounds.

EXAMPLE 4 dl-Tricyclic Lactone Acetal (Formula V: R₁ and R₂ are methyland ˜ is endo), and Tricyclic Lactone Aldehyde (Formula VI: ˜ is endo).

Refer to Chart A. A solution of the Formula-IV product of Example 3 (56g.) in dichloromethane (400 ml.) is treated with potassium bicarbonate(40 g.) and cooled to 10° C. A solution of meta-chloroperbenzoic acid(55 g. of 85%) in dichloromethane (600 ml.) is added over 40 min. Themixture is stirred at 10° C. for 1 hr., then warmed to reflux for 40min. The mixture is cooled and filtered, and the filtrate is washed with5% aqueous sodium bicarbonate-sodium thiosulfate, and then water. Thedichloromethane layer is dried over anhydrous sodium sulfate, andconcentrated to the Formula-V acetal (61 g.). A portion (58 g.) ischromatographed on 2 kg. of silica gel packed in ethyl acetateSkellysolve B (50-50). Elution with 50-50, 70-b 30 and 80-20 ethylacetate-Skellysolve B yields a fraction (24.9 g.) shown by NMR to be amixture of dimethyl acetal (V) and aldehyde (VI). A portion (22.6 g.) ofthe mixture is dissolved in 100 ml. of (60-40) formic acid-water andallowed to stand 1 hr. at 25° C. The solution is then concentrated undervacuum and the residue taken up in dichloromethane. The dichloromethanesolution is washed with 5% aqueous sodium bicarbonate and water, driedover sodium sulfate, and concentrated to a brown oil (17.5 g.) whichcrystallizes on seeding. Trituration of the crystals with benzene leavescrystals of the Formula-VI aldehyde (9.9 g.). An analytical sample isobtained by recrystallization from tetrahydrofuran, m.p. 72°-74° C.(corr.); infrared absorption peaks at 2740, 1755, 1710, 1695, 1195,1165, 1020, 955, and 910, cm⁻ ¹ ; NMR peaks at 1.8-3.4, 5.0-5.4, and9.92 δ.

Following the procedures of Example 4 but using the exo Formula-IVlactone acetal compound, there is obtained the corresponding exoFormula-V lactone acetal.

Likewise, following the procedures of Example 4 using the exo Formula-Vcompound, there is obtained the corresponding exo Formula-VI lactonealdehyde.

Following the procedures of Example 4 but using the Formula-IV compoundsdisclosed following Example 3, there are obtained the correspondingFormula-V compounds, and, thence, the corresponding Formula-VI lactonealdehydes.

EXAMPLE 5 dl-Tricyclic Lactone Heptene (Formula VII: Y is 1-pentyl and ˜is endo).

Refer to Chart A. A suspension of n-hexyltriphenylphosphine bromide (6.6g.) in 20 ml. of benzene is stirred under nitrogen and to it is added 10ml. of 1.6 m. n-butyl-lithium in n-hexane. After 10 min. a benzenesolution of the Formula-VI tricyclic aldehyde (1.66 g.) of Example 4 isadded dropwise over 15 min. and the reaction mixture is heated at65°-70° C. for 2.5 hrs. The mixture is cooled, the solids are filteredoff and washed with benzene, and the combined filtrate and washes areextracted with dilute hydrochloric acid and water. The solution is driedover sodium sulfate and concentrated under vacuum to an oil (3.17 g.).The crude Formula-VII product is chromatographed on 400 g. of silica gelpacked with (30-70) ethyl acetatecyclohexane and eluted with the samemixture. Fractions of 20 ml. volume are collected. Fractions 47-50 arefound to contain 0.8 g. of the desired Formula-VII tricyclic lactoneheptene; NMR peaks at 0.6-3.0, 4.4- 5.1, and 5.4 δ. To minimize sidereactions, it is preferred that the Wittig reagent prepared from thephosphonium bromide and n-butyl-lithium be filtered to remove lithiumbromide, and that the resultant solution be added to the benzenesolution of the Formula-VI tricyclic aldehyde in equivalent proportions.

Following the procedures of Example 5 but using the exo Formula-VIcompound, there is obtained the corresponding exo Formula-VII lactoneheptene. A preferred source of the exo form of the Formula-VI tricycliclactone aldehyde is by the steps shown in Chart H. Therein R₁₄ is alkylof one to 4 carbon atoms. Thus, diazoacetic acid ester is added to adouble bond of cyclopentadiene to give an exo-endo mixture of theFormula-XXXI bicyclo[3.1.0]hexene substituted at 6 with an esterifiedcarboxyl, e.g. a methyl ester wherein R₁₀ is methyl. The exo-endomixture is treated with a base to isomerize the endo isomer to more ofthe exo isomer. Next the hexene is reacted with Cl₂ C=C=O generated insitu from dichloroacetyl chloride and a tertiary amine or fromtrichloroacetyl chloride and zinc dust as in step b of Chart A, to theFormula-XXXII dichloroketone. Successively, the dichloroketone isreduced as in step c of Chart A; the resulting Formula-XXXIII tricyclicketone is converted to a lactone ester as in step d of Chart A; thelactone is saponified, then acidified, to yield the Formula-XXXVcompound with a carboxyl group at the 6-position; then the carboxylgroup is transformed to an alcohol group and finally to the exo aldehydeof Formula XXXVII.

CHART H ##SPC35## EXAMPLE 6 dl-Tricyclic Glycols (Formula VIII: W is1-pentyl and ˜ is endo). Refer to Chart A.

Procedure A. A solution of the Formula-VII tricyclic lactone heptene ofExample 5 (0.8 g.) in 10 ml. of benzene is treated with osmium tetroxide(1.0 g.) in 15 ml. of benzene. After standing 24 hrs., the mixture istreated with hydrogen sulfide for 30 min., then filtered to remove ablack solid. The filtrate is evaporated to an oil (393 mg.). Anadditional quantity of oil (441 mg.) is recovered by suspending theblack solid in ethyl acetate and again treating with hydrogen sulfide.The oil is chromatographed on 100 g. of silica gel packed and elutedwith (40-60) acetone-dichloromethane. Fractions of 20 ml. volume arecollected. Two erythro glycols of Formula VIII are recovered, one morepolar (slower-moving on the column) than the other. The faster-movingglycol, 0.3 g., is found in fractions 20-30; the slower-moving one, 0.28g., in fractions 31- 40.

Procedure B. A mixture of 7 ml. of N-methylmorpholine oxide-hydrogenperoxide complex (see Fieser et al., "Reagents for Organic Syntheses,"p. 690, John Wiley and Sons, Inc., New York, N.Y. (1967)), 8 ml. of THF,14 ml. of tert-butanol, and osmium tetroxide (2mg.) in 2 ml. oftert-butanol is cooled to about 15° C.

A solution of the Formula-VII tricyclic lactone heptene of Example 5(3.95 g.) in 12 ml. of THF and 12 ml. tert-butanol is then added slowlyover a period of 2 hrs. at a temperature of 15°-20° C. The mixture isstirred for an additional 2 hrs., and to it is added a slurry of filteraid (for example magnesium silicate, 0.8 g.) in 14 ml. of watercontaining sodium thiosulfate (0.4 g.), and the solids removed byfiltration. The filtrate is concentrated under reduced pressure to anoil. Water (200 ml.) is added and the oil-water mixture is extractedwith several portions of dichloromethane. The dichloromethane solutionis dried over magnesium sulfate and then concentrated under reducedpressure to a mixture containing the title products.

Following the procedures of Example 6A and 6B but using the exoFormula-VII compound, there are obtained the corresponding exoFormula-VIII tricyclic glycols.

EXAMPLE 7 dl-Bicyclic Lactone Bismesylate (Formula IX: R₉ is methyl, Wis 1-pentyl, and ˜ is endo), and Bicyclic Lactone Diol (Formula X: W is1-pentyl and ˜ indicates the α configuration.

Refer to Chart A. The slower moving Formula-VIII erythro glycol fromExample 6 (277 mg.) is dissolved in 5 ml. of pyridine, cooled to 0° C.under nitrogen, and treated with methanesulfonyl chloride (0.89 g.). Themixture is stored at 0° C. for 20 hrs., ice water (0.6 ml.) is added andthe mixture stirred an additional 20 min. Then the mixture is pouredinto dichloromethane and washed with ice-cold 1 N. hydrochloric acid,ice-cold 5% sodium bicarbonate solution, and ice water. The solution isdried and concentrated under vacuum to an oil (290 mg.), consisting ofthe Formula IX bis-mesylate compound.

The above product is dissolved in 10 ml. of acetone and 5 ml. of water,left standing for 3 hrs. at 25° C., and concentrated under reducedpressure to remove the acetone. The solution is diluted with water andextracted with dichloromethane. The dichloromethane solution is washedwith 5% sodium bicarbonate solution and brine, dried, and concentratedunder vacuum to an oil (200 mg.), consisting of the Formula-X product.

The Formula-X compound is obtained as a mixture of isomers in the α andβ configuration. They are separated by silica gel chromatography and areused separately, e.g. in preparing the Formula-XIIbis(tetrahydropyranyl) ether. The undesired Formula-X isomer is recycledto isomerize it to a mixture of the α and β forms. For theisomerization, the 15-hydroxyl is oxidized to a 15-keto with selectiveoxidant, e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activatedmanganese dioxide, or nickel peroxide (see Fieser et al., "Reagents forOrganic Syntheses," John Wiley and Sons, Inc., New York, N.Y., pp. 215,637, and 731). Thereafter, the 15-keto compound is reduced with zincborohydride, by methods known in the art, to a mixture of the α and βisomers, which are then separated by silica gel chromatography.

Following the procedure of Example 7, the faster-moving glycol istransformed to the same Formula-X product as above.

Following the procedures of Example 7 but using the exo Formula-VIIIcompound, there is obtained the corresponding exo Formula-IXbismesylate. This exo bismesylate is transformed to the Formula-Xlactone diol by the procedures of Example 7 used for the endo compound.

The Formula-X lactone diol wherein W is 1-pentyl is transformed todl-PGE₂.sub.α] and dl-PGF₂.sub.α and their alkyl esters using methodsgenerally known in the art, e.g., following the steps of Chart C fordl-PGE₂.sub.α 2 and Chart E for dl-PGF₂.sub.α.

EXAMPLE 8 dl-Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde Acetal of2,2-dimethyl-1,3-propanediol (Formula II: R₁ and R₂ taken together are--CH₂ --C(CH₃)₂ --CH₂ --and ˜ is endo).

Refer to Chart A. A solution of Formula-Iendobicyclo[3.1.0]hex-2-ene-6-carboxaldehyde (48.6 g.),2,2-dimethyl-1,3-propanediol (140.4 g.), and oxalic acid (0.45 g.) inbenzene (0.9 1.) is heated under reflux for 4 hrs. The azeotropicallydistilled water is removed in a water separator. The reaction mixture iscooled, washed with 5% sodium bicarbonate solution and water. Thebenzene solution is dried over sodium sulfate, concentrated to an oil(93 g.), and distilled at reduced pressure. The fraction boiling at88°-95° C./0.5 mm. is the desired title compound, 57.2 g., m.p. 53°-55°C.; NMR peaks at 0.66, 1.2, 3.42, 3.93, and 5.6 δ; infrared absorptionat 1595, 1110, 1015, 1005, 990, 965, 915 and 745 cm.sup.⁻¹.

Following the procedures of Example 8 but using the exo Formula-Icompound, there is obtained the corresponding exo Formula-II acetal.

EXAMPLE 9 d7-Tricyclic Dichloroketone (Formula III: R₁ and R₂ takentogether are --CH₂ --C(CH₃)₂ --CH₂ --and ≠ is endo).

Refer to Chart A. Following the procedures of Example 2, the Formula-IIcompound of Example 8 is transformed to the title compound, m.p.97°-100° C., NMR peaks at 0.75, 1.24, 2.43 (multiplet), 3.42, 3.68, and3.96 (doublet) δ; infrared absorption at 3040, 1810, 1115, 1020, 1000,980, 845, and 740 cm.sup.⁻¹.

EXAMPLE 10 dl-Tricyclic Ketone (Formula IV: R₁ and R₂ taken together are--CH₂ --C(CH₃)₂ --CH₂ --and ˜ is endo).

Refer to chart A. Following the procedure of Example 3, the Formula-IIIdichloroketone of Example 9 is transformed to the title compound, anoil; NMR peaks at 0.75, 1.25, 3.0 (multiplet) and 4.0 (doublet) δ;infra-red absorption at 1170 cm.sup.⁻¹.

Following the procedures of Examples 3 and 10 but using thecorresponding exo Formula-III compound, there is obtained thecorresponding exo Formula-IV tricyclic ketone.

EXAMPLE 10A dl-Tricyclic Lactone Acetal (Formula V: R₁ and R₂ takentogether are --CH₂ --C(CH₃)₂ --CH₂ -- and ˜ is endo) and TricyclicLactone Aldehyde (Formula VI: ˜ is endo).

Refer to chart A. Tricyclic ketone IV (Example 10, 12 g.) together withpotassium bicarbonate (6.1 g.) in 100 ml. of dichloromethane is cooledto about 10° C. Metachloroperbenzoic acid (12.3 g. of 85%) is addedportionwise at such a rate that the reaction temperature is kept below30° C. Thereafter the mixture is stirred for 1 hr. and to it is added150 ml. of 5% aqueous sodium bicarbonate solution containing 9 g. ofsodium thiosulfate. The dichloromethane layer is dried over sodiumsulfate and concentrated under reduced pressure. The oily residuecontains the Formula-V lactone acetal: NMR peaks at 0.75, 1.23, 3.5(quartet), 3.9 (doublet) and 4.8 (quartet) δ; infrared absorption at1760 cm.sup.⁻¹.

Lactone acetal V (about 4.4 g.) in 60 ml. of 88% formic acid is leftstanding at 50° C. for one hour. The solution is then cooled, dilutedwith 60 ml. of 1 N. sodium hydroxide saturated with sodium chloride, andextracted with dichloromethane. The combined extracts are washed with10% sodium carbonate, dried over sodium sulfate, and concentrated underreduced pressure. The product crystallizes on standing, yielding theFormula-VI lactone aldehyde: m.p. 69°-73° C., NMR peaks at 5.2(multiplet) and 10.0 (doublet) δ, and infrared absorption at 1755cm.sup.⁻¹.

Following the procedures of Example 10A, the corresponding exoFormula-IV tricyclic ketone yields the corresponding Formula-V and -VIcompounds.

EXAMPLE 11 dl-PGE₃, dl-15-epi-PGE₃, and their Alkyl Esters (Formula XXIIof Chart D: ˜ indicates the 15α or 15β configuration).

Refer to Charts A and D. Following the procedures of Examples 1-4,inclusive, the endo Formula-I bicyclohexene aldehyde is transformed tothe endo Formula-VI tricyclic lactone aldehyde.

Following the procedure of Example 5, but substituting for then-hexyltriphenylphosphine bromide the unsaturated phosphonium compoundderived from 1-bromo-3-hexyne, viz. 1-hex-3-ynyltriphenylphosphinebromide, there is obtained the Formula-VII heptenyne compound wherein Yis 1-pent-2-ynyl and ˜ is endo.

Successively, following the procedures of Examples 6 and 7, there areformed the Formula-VIII, -IX, and -X compounds wherein W is1-pent-2-ynyl and ˜ is endo for the moiety on the cyclopropane ring, andrepresents either the α or β configuration for the hydroxyl group on thesidechain. The Formula-X octenyne diol is obtained as a mixture ofisomers in the α and β configuration. They are separated by silica gelchromatography and are used in preparing the Formula-XVII compounds. Theundesired Formula-X isomer is recycled and isomerized using theprocdures of Example 7. The α-configuration Formula-X ocetenyne diolwherein W is 1-pent-2-ynyl is reduced to the Formula-XVII octadiene diolwherein Z is 1-pent-2-enyl by reducing the --C.tbd.C-- moiety to cis--CH=CH-- by hydrogenation over Lindlar catalyst as follows. To asolution of the Forumula-X compound (20 mg.) in methanol (2 ml.) isadded 5 mg. of 5% palladium-on-barium sulfate and 2 drops of syntheticquinoline. The mixture is stirred at about 25° C. and atmosphericpressure. The reaction is terminated when one equivalent of hydrogen isabsorbed. The mixture is filtered and the filtrate concentrated undervacuum. Ethyl acetate is added and the solution is chromatographed onsilica gel impregnated with silver nitrate. The column is developed withisomeric hexanes (Skellysolve B) containing increasing amounts of ethylacetate. Those fractions containing the desired octadiene diol arecombined and concentrated to yield the Formula-XVII intermediate.

Following the steps of Chart D, the Formula-XVII compound, wherein Z is1-pent-2-enyl and ˜ represents the α configuration, is transformed toPGE₃ using methods generally known in the art. Thus, the Formula-XVIIdiol is converted to the Formula-XVIII bis(tetrahydropyranyl) ether; theoxo group of the lactone is reduced to form the Formula-XIX lactol; theFormula-XX compound is formed by a Wittig reaction using ω-chloro orω-bromopentanoic acid; the Formula-XX 9-hydroxy group is oxidized to the9-keto group of the Formula-XXI intermediate; and, finally, theprotective tetrahydropyranyl groups are removed by hydrolysis to yieldthe desired Formula-XXII dl-PGE₃.

Following the procedures of Example 11, but substituting the exoFormula-I aldehyde for the endo aldehyde, there are obtained theFormula-VI, -VII, -VIII and -IX exo compounds which are converted to theFormula-X lactone diol, and thence to dl-PGE₃.

Following the procedures of Example 11 for dl-PGE₃, but substituting the15β (R)-configuration Formula-X octenyne diol for the S-configurationcompound, there are formed any of the Formula-XVII-to-XXI intermediateswherein ˜ indicates the β configuration, and thence dl-15β-PGE₃ ofFormula-XXII wherein ˜ indicates the β configuration.

Although Example 11 illustrates one embodiment of the process forpreparing PGE₃, wherein the --C.tbd.C-- moiety of the Formula-X octenynediol is reduced to cis --CH=CH-- immediately before forming thecis(tetrahydropyranyl) ether, it is within the scope of this inventionas shown in Charts A and D to carry out that reduction of --C.tbd.C-- tocis --CH=CH-- at any stage between the Formula-VIII glycol and the finaldl-PGE₃ or dl-15β-PGE₃.

Thus, the Formula-VIII compound wherein W is 1-pent-2-ynyl and ˜indicates attachment of the moiety to the cyclopropane ring in exo orendo configuration, is subjected successively to the followingreactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R₉ O₂S--, wherein R₉ is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0° to 60° C. toform a bicyclic lactone diol;

c. separation of the diols of α (S) and β (R) configuration;

d. transformation to a bis(tetrahydropyranyl) ether;

e. reduction of the lactone oxo group to a hydroxy group;

f. Wittig alkylation with a compound of the formula Hal-- (CH₂)₄ --COOHwherein Hal is bromo or chloro;

g. oxidation of the 9-hydroxy to oxo; and

h. transformation of the two tetrahydropyranyloxy group to hydroxygroups;

with the proviso that, before or after any of the steps a to h, the--C.tbd.C-- moiety is reduced to cis --CH=CH--, thereby forming dl-PGE₃or dl-15β-PGE₃. By these procedures, there are formed the intermediatesof Formulas VIII, IX, and X, wherein W is either cis 1-pent-2-enyl or1-pent-2-ynyl; and the intermediates of Formulas XVIII, XIX, XX, andXXXI, wherein Z is either cis 1-pent-2-enyl or 1-pent-2ynyl.

EXAMPLE 12 dl-PGF₃.sub.α and dl-15-epi-PGF₃.sub.α Esters (Formula XXVIof Chart E: ˜ indicates the 15α (S) or 15β (R) configuration).

Refer to Chart E. Following the procedures of Example 11, there isprepared the α-configuration Formula-XVII octadiene diol. This diol istransformed to PGF₃.sub.α by the steps shown in Chart E wherein ˜indicates the α configuration, using methods known in the art. Thus, theFormula- XVII diol is converted to the Formula-XXV lactol by reducingthe oxo group of the lactone; and the Formula-XXV compound is convertedto dl-PGF₃.sub.α (Formula XXVI wherein ˜ indicates the S configuration)by a Wittig reaction using ωchloro- or ω-bromo-pentanoic acid.

Following the procedures of Example 12, but substituting theβconfiguration Formula-XVII octadiene diol for the α-configurationFormula-XVII octadiene diol, there is obtained dl-15β-PGF₃.sub.α(Formula XXVI wherein ˜ indicates the β configuration).

Although Example 22 illustrates one embodiment of the process forpreparing PGF₃.sub.α, wherein the --C.tbd.C-- moiety of the Formula-Xoctenyne diol is reduced to cis --CH=CH-- immediately before reducingthe lactone oxo group to a hydroxy group, it is within the scope of thisinvention as shown in Charts A and F to carry out the reduction of--C.tbd.C-- to cis --CH=CH-- at any stage between the Formula-VIIIglycol and the final dl-PGF₃.sub.α and dl-15β-PGF₃.sub.α. Thus, theFormula-VIII compound wherein W is 1-pent-2-ynyl and ˜ indicatesattachment of the moiety to the cyclopropane ring in exo or endoconfiguration is subjected successively to the following reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R₉ O₂S--, wherein R₉ is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0° to 60° C. toform a bicyclic lactone diol;

c. separation of the diols of α and β configuration;

d. reduction of the lactone oxo group to a hydroxy group; and

e. Wittig alkylation with a compound of the formula Hal-- (CH₂)₄ --COOHwherein Hal is bromo or chloro;

with the proviso that, before or after any of the steps a to e, the--C.tbd.C-- moiety is reduced to cis --CH=Ch--, thereby formingdl-PGF₃.sub.α or dl-15β-PGF₃.sub.α. By these procedures, there is formedthe Formula-XXV intermediate wherein Z is either cis 1-pent-2-enyl or1-pent-2-ynyl.

EXAMPLE 13 Resolution of Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde(Formula 1: ˜ is endo).

A. Formula-I endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde (12.3 g.) andl-ephedrine (16.5 g.) are dissolved in about 150 ml. of benzene. Thebenzene is removed under vacuum and the residue taken up in about 150ml. of isopropyl ether. The solution is filtered, then cooled to -13° C.to yeild crystals of2-endo-bicyclo[3.1.0]hex-2-en6-yl-3,4-dimethyl-5-phenyl-oxazolidine,11.1 g., m.p. 90° - 92° C. Three recrystallizations from isopropylether, cooling each time to about -2° C., yield crystals of theoxazolidine, 2.2 g., m.p. 100°-103° C., now substantially a singleisomeric form as shown by NMR.

The above re-crystallized oxazolidine (1.0 g.) is dissolved in a few ml.of dichloromethane, charged to a 20 g. silica gel column and eluted withdichloromethane. The silica gel is chromatography-grade, (Merck),0.05-0.2 mm. particle size, with about 4-5 g. water per 100 g. Fractionsof the eluate are collected, and those shown by thin layerchromatography (TLC) to contain the desired compound are combined andevaporated to an oil (360 mg.). This oil is shown by NMR to be desiredFormula-I compound, endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde,substantially free of the ephedrine, in substantially a singleopticallyactive isomeric form; called "the isomer of Example 13-A"herein. Points on the circular dichroism curve are (λ in nm, θ ): 350,0; 322.5, -4,854; 312, -5,683; 302.5, -4,854; 269, 0; 250, 2,368; 240,0; and 210, -34,600.

B. The mother liquors of the oxazolidine are combined and evaporated tocrystals, taken up in dichloromethane, and chromatographed on silica gelas above to yield the enantiomorph of the above Formula-I compound,having the opposite optical rotation.

C. A preferred method of obtaining the isometic oxazolidine which yieldsthe aldehyde of optical rotation opposite to that of the isomer ofExample 13-A is as follows. Following the procedure of A, above, theracemic aldehyde is reacted with d-ephedrine to produce the oxazolidinein its diastereomeric forms. Recrystallization then yields the desiredoxazolidine, which is converted by hydrolysis to the desired opticallyactive aldehyde.

Following the procedures of Example 13, the exo Formula-Ibicyclo[3.1.0]hex-2-ene-6-carboxaldehyde is converted to the oxazolidineof d- or l-ephedrine and resolved into its optically active isomers.

EXAMPLE 14 Resolution of Acetal Ketone (Formula IV: R₁ and R₂ takentogether are --CH₂ --C(CH₃)₂ --CH₂ -- and ˜ is endo).

A. A solution of 2.34 g. of the Formula-IV acetal ketone of Example 10(wherein the acetal is prepared from 2,2-dimethyl-1,3-propanediol) andl-ephedrine (1.65 g.) in benzene (15 ml.), together with 1 drop ofacetic acid, is heated at reflux for about 5.5 hrs., using a Dean andStark trap to remove water. The benzene is then removed by evaporationleaving the formed oxazolidine as solids which are dissolved inmethanol. On cooling the methanol solution, there is obtained one of thediastereomeric oxazolidines, 1.57 g., m.p. 161°-166° C. [α _(D).sup.25 - 7.5° in chloroform, now substantially a single isomeric form asshown by NMR. NMR peaks at 0.63 (doublet), 0.72, 1,23, 2,38, 3,52, 3,95(doublet) and 4.94 (doublet) δ

Following the procedure of Example 13, the above crystallizedoxazolidine is converted on a silica gel column to an optically activeisomer of the desired Formula-IV compound, 0.56 g., m.p. 43°-47° C.[α]_(D) ²⁵ + 83° in chloroform; called "the isomer of Example 14-A"herein.

B. The mother liquor from A is concentrated and chilled to -13° C., toyield another diastereomeric oxazolidine, 1.25 g., m.p. 118°-130° C.,[α]_(D) ²⁵ +11.7° in chloroform; NMR peaks at 0.63 (doublet), 0.72,1.23, 2.38, 3.52, 3,99 (doublet) and 5.00 (doublet) δ.

Following the procedure of Example 13, the crystallized oxazolidine isconverted on a silica gel column to an optically active isomer of theFormula-IV compound.

C. Reaction of the above Example 14-B isomer with d-ephedrine by theprocedure of Example 14-A yields the enan-tiomorph of the oxazolidine ofExample 14A, m.p. 165° C., [α]_(D) ²⁵ + 7.5° in chloroform.

Following the procedure of Example 13, the crystallized oxazolidine isconverted on a silica gel column to an optically active isomer of thedesired Formula-IV identical to that obtained in Example 14-B above.

Following the procedures of Example 14, the exo Formula-IV acetal ketoneof Example 10 is converted to the oxazoldine of d- or l-ephedrine andresolved into its optically active isomers.

Any one of the above resolved oxazolidines is hydrolyzed to the oxocompound and ephedrine by contact with water, preferably with an acidcatalyst, as is known in the art (see Elderfeld, Heterocyclic Compounds,Vol. 5, page 394, Wiley, N.Y., 1957). Thus, the oxazolidine ofl-ephedrine and the Formula-IV acetal ketone (Example 14A, 5.0 g.) isstirred in a solution of tetrahydrofuran-water-acetic acid (25 ml.: 25ml.: 5 ml.) for 4 hrs. at about 25° C. under nitrogen. The solvents areremoved under reduced pressure at 25°-40° C., and the residue is mixedwith 25 ml. of water. The mixture is extracted several times withbenzene, and the combined benzene layers are washed with water, driedover sodium sulfate, and finally concentrated under reduced pressure tothe optically active Formula-IV acetal ketone having the same propertiesas reported above following section A. An alternate method ofhydrolyzing the oxazolidine is on a silica gel-water column according toExample 13, thereafter eluting the released oxo compound and recoveringsame by conventional means.

EXAMPLE 15 Resolution of Tricyclic Lactone Aldehyde 16 (Formula Vl: ˜ isendo).

A. A solution of the endo Formula-VI lactone aldehyde (0.5 g.) ofExample 4 and l-ephredrine (0.5 g.) in benzene (20 ml.) is concentratedunder vacuum to a residue. The residue is treated with diethyl ether toyield crystals of an oxazolidine mixture. Recrystallization of themixture from methanol yields an oxazolidine, m.p. 133.5-134.5.Thereafter, hydrolysis of the oxazolidine on a silica gel columnfollowing the procedure of Example 13 yields an optically active isomercorresponding to the mirror image of the Formula-VI lactone aldehyde,which is thereafter recovered by conventional means and is hereinafteridentified as the "isomer of Example 15-A".

B. Following the procedure of Example 15-A, but replacing l-ephedrinewith d-ephedrine in preparing the oxazolidine, the optically activeisomer corresponding to the Formula-VI lactone aldehyde is obtained,hereinafter identified as the "isomer of Example 15 -B".

Following the procedures of Example 15, the exo Formula-VI lactonealdehyde is resolved into its optically active isomers.

EXAMPLE 16 Optically Active Tricyclic Glycol (Formula VIII of chart a: Wis 1-pentyl and ˜ is endo); PGE₂, PGF₂ .sub.α, their ent-Compounds andtheir 15-Epimers.

Refer to chart C. Following the procedures of Examples 1 to 6,incclusive, but using the Formula-I endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde isomer of Example 13-A, there isobtained the Formula-VIII tricyclic glyhcol, wherein W is 1-pentyl and ˜is endo, as an optically active isomer. Following the procedures ofExample 7, this isomer is transformed to the optically active Formula-IXand Formula-X compounds wherein W is 1-pentyl.

Likewise, using the Formula-I isomer of Example 13-C, there are obtainedthe enantiomorphic Formula-VIII, -IX, and -X compounds.

Each of the Formula-X isomers is transformed to the corresponding PGE₂,ent-PGE₂, and their 15-epimers, using methods known in the art by thesteps shown in Chart C. Thus, PGE₂ is obtained from the optically activeFormula-X diol prepared from the Formula-I aldehyde isomer of Example13-A; ent-PGE₂ is obtained from the enantiomorphic Formula-X diolprepared from the Formula-I aldehyde isomer of Example 13-C.

Furthermore, again using the optically active Formula-VIII, -IX, and -Xcompounds prepared above, but following the steps of Chart E, usingmethods generally known in the art, there are obtained the correspondingPGF₂ .sub.α, ent-PGF₂ .sub.α, and their 15-epimers.

Following the procedures of Examples 1 to 6, inclusive, but substitutingthe optical isomers of the exo Formula-I aldehyde of Example 13 for theendo aldehyde, there are obtained the corresponding optically active exoFormula-VIII tricyclic glycols and Formula-IX bismesylates, which areconverted to the isomeric Formula-X diols and thence to thecorresponding PGE₂, ent-PGE₂, and their 15-epimers, PGF₂, PFG₂ .sub.αand their 15-epimers.

EXAMPLE 17 PGE₃, ent-PGE₃ and their 15-Epimers, (Formula XXII of ChartD: ˜ indicates the α or β configuration).

Refer to Chart D. Following the procedures of Example 13, the endoFormula-I bicyclohexene aldehyde is resolved into its two opticallyactive isomeric forms. Following the procedures of Example 11 andthereafter, each of the Formula-I isomers is transformed to thecorresponding Formula-X diol in its α and β configurations and thence tothe corresponding PGE₃, ent-PGE₃, and their 15-epimers.

Following the procedures of Examples 14 and 15, the endo Formula-IVacetal ketone or the Formula-VI lactone aldehyde are resolved into theirrespective optically active isomeric forms. Following the procedures ofExample 11 and thereafter, each of the Formula-IV or Formula-VI isomersis transformed to the corresponding Formula-X diol in its α and βconfigurations and thence to the corresponding PGE₃, ent-PGE₃, and their15-epimers.

Thus, PGE₃ is obtained from the optically active Formula-X diol preparedfrom the Formula-IV Acetal ketone of Example 14-A or the Formula-VIlactone aldehyde of Example 15-B; ent PGE₃ is obtained from theenantiomorphic Formula-X diol prepared from the Formula-IV acetal ketoneof Example 14-C or the Formula-VI lactone aldehyde of Example 15-A.

Likewise, employing the exo forms of the Formula-I, -IV, and -VIcompounds, these are resolved into their respective optically activeisomeric forms and transformed to the corresponding Formula-X diol andthence to the corresponding PGE₃, ent-PGE₃, and their 15-epimers.

Likewise, following the procedures of Example 11 and thereafter, theoptically active Formula-VIII glycol in its isomeric forms, wherein W is1-pent-2-ynyl and ˜ indicates attachment of the moiety to thecyclopropane ring in exo or endo configuration is subject successivelyto the following reactions:

a. replacement of the glycol hydrogens by an alkane-sulfonyl group, R₉O₂ S--, wherein R₉ is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0° to 60° C. toform a bicyclic lactone diol;

c. separation of the diols of α and β configuration;

d. transformation to a bis(tetrahydropyranyl) ether;

e. reduction of the lactone oxo group to a hydroxy group;

f. Wittig alkylation with a compound of the formula Hal--(CH₂)₄ --COOHwherein Hal is bromo or chloro;

g. oxidation of the 9-hydroxy to oxo; and

h. transformation of the two tetrahydropyranyloxy groups to hydroxygroups;

with the proviso that, before or after any of the steps a to h, the--C.tbd.C-- moiety is reduced to cis --CH=CH--, thereby forming PGE₃,ent-PGE₃, or their 15-epimers.

EXAMPLE 18 PGF₃.sub.α, ent-PGF₃.sub.α, and their 15-epimers, (FormulaXXVI of Chart F: ˜ indicates the α or β configuration).

Refer to Chart F. Following the procedures of Example 13, the endoFormula-I bicyclohexene aldehyde is resolved into its two opticallyactive isomeric forms. Following the procedures of Example 12 andthereafter, each of the Formula-I isomers is transformed to thecorresponding Formula-X diol in its α and β configurations and thence tothe corresponding PGF₃.sub.α, ent-PGF₃.sub.α, and their 15-epimers.

Following the procedures of Examples 14 and 15, the endo Formula-IVacetal ketone or the Formula-VI lactone aldehyde are resolved into theirrespective optically active isomeric forms. Following the procedures ofExample 12 and thereafter, each of the Formula-IV or Formula-VI isomersis transformed to the corresponding Formula-X diol in its α and βconfiguration and thence to the corresponding PGF₃.sub.α,ent-PGF₃.sub.α, and their 15-epimers.

Likewise, employing the exo forms of the Formula-I, -IV, and -VIcompounds, these are resolved into their respective optically activeisomeric forms and transformed to the corresponding Formula-X diol inits α and β configuration and thence to the corresponding PGF₃.sub.α,ent-PGF₃.sub.α and their 15-epimers.

Likewise, following the procedures of Example 12 and thereafter, theoptically active Formula-VIII glycol in its isomeric forms, wherein W is1-pent-2-ynyl and ˜ indicates attachment of the moiety to thecyclopropane ring in exo or endo configuration is subjected successivelyto the following reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R₉ O₂S--, wherein R₉ is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0° to 60° C. toform a bicyclic lactone diol of S and R configuration;

c. separation of the diols of S and R configuration;

d. reduction of the lactone oxo group to a hydroxy group; and

e. Wittig alkylation with a compound of the formula Hal--(CH₂)₄ --COOHwherein Hal is bromo or chloro;

with the proviso that, before or after any of the steps a to e, the--C.tbd.C-- moiety is reduced to cis --CH=CH--, thereby formingPGF₃.sub.α, ent-PGF₃.sub.α, or their 15-epimers.

EXAMPLE 19 dl-Tricyclic Lactone Epoxide (Formula XXXVIII: Y is n-pentyl,˜ indicates attachment to the cyclopropane ring in exo or endoconfiguration, and ##EQU7## indicates attachment of the epoxide oxygento the side chain in α or β configuration).

Refer to Chart B. A mixture of the Formula-VII tricyclic lactone hepteneof Example 5 (2.02 g.) and potassium bicarbonate (0.8 g.) in 12 ml. ofdichloromethane is treated with peracetic acid (2 ml. of 40% in 8 ml. ofdichloromethane) added dropwise over 10 min. After the starting materialhas been converted to the product as shown by TLC (about 45 hrs. at 25°C), the mixture is diluted with 30 ml. of dichloromethane and washedtwice with 5% sodium bicarbonate containing sodium thiosulfate (0.5 g.).The dichloromethane solution is dried over anhydrous sodium sulfate andconcentrated under reduced pressure to a residue of the title product,2.18 g., NMR peaks at 0.6-3.3, 4.8 (broad) δ.

EXAMPLE 20 dl-Bicyclic Lactone Diformate (Formula XL: Y is n-pentyl and˜ is alpha and beta). Refer to Chart B.

Procedure A -- A solution of the mixed Formula-VIII glycols (FormulaXXXIX wherein M and E are hydrogen) of Example 6 (2.38 g.) in 40 ml. of100% formic acid is left standing 5.5 hrs. at about 25° C. The mixtureis then concentrated under reduced pressure to an oily residue. Theresidue is treated with a solution of phosphate buffer (pH 6.8) andabout 10% sodium bicarbonate and extracted with dichloromethane. Thedichloromethane solution is dried over sodium sulfate and concentratedunder reduced pressure to a residue containing the title product, 2.66g.

Procedure B -- A solution of the Formula-XXXVIII epoxide of Example 19(10.0 g.) in 80 ml. of a mixture of acetone-water-formic acid (70:30:2by volume) is left standing 55 min. at about 25° C. The mixture isconcentrated under reduced pressure to a residue. The residue is treatedwith 5% sodium bicarbonate, saturated with sodium chloride, andextracted with ethyl acetate. The ethyl acetate solution is dried overmagnesium sulfate and concentrated under reduced pressure to a mixtureof glycol XXXIX (M and E are hydrogen) and diol X, 11.7 g.

A solution of the above glycol-diol mixture in 350 ml. of 100% formicacid is left standing 2 hrs. at about 25° C. The mixture is thenconcentrated under reduced pressure and the residue taken up indichloromethane. The dichloromethane solution is washed with 5% sodiumbicarbonate, dried over sodium sulfate and concentrated to a residuecontaining the title product, 13.2 g.

Procedure C -- A solution of the Formula-XXXVIII epoxide of Example 19(2.18 g.) in 40 ml. of 100% formic acid (see for example Winstein etal., J. Am. Chem. Soc. 74, 1120 (1952)) is stirred under nitrogen for2-3 hrs. at about 25° C., monitoring the reaction by TLC. The mixture isconcentrated under reduced pressure to a residue. The residue is takenup in 50 ml. of dichloromethane and the solution washed with 5% sodiumbicarbonate. The dichloromethane solution is dried over sodium sulfateand concentrated under reduced pressure to a residue containing theFormula-XL title product, 2.92 g.

EXAMPLE 21 dl-Bicyclic Lactone Diol (Formula X: W is 1-pentyl and ˜ isalpha or beta).

Refer to Chart B. A solution containing the Formula-XL diformates ofExample 20 (2.92 g.) in 10 ml. of methanol is stirred with potassiumbicarbonate (0.2 g.) for 0.5 hr. The mixture is then filtered and thefiltrate is diluted with 50 ml. of dichloromethane. The solution iswashed with brine, dried over magnesium sulfate, and concentrated underreduced pressure to a residue. The residue is chromatographed on silicagel (810 g.) packed in acetone-dichloromethane (30:70), eluting withacetone-dichloromethane (30--45% acetone) and collecting 200 ml.fractions. Fractions shown by TLC to contain the desired products freeof starting materials and impurities are combined, for example fractions20--25 contain the X.sub.β title compound and fractions 26-35 containthe X.sub.α title compound. Concentration of the respective fractionsyields the title compounds: diol X.sub.β, 0.66 g.; diol X.sub.α, 0.76 g.

EXAMPLE 22 dl-Tricyclic Lactone Monoformate (FIG. XXXIX: M and E arehydrogen or formyl, Y is 1-pentyl, and ˜ indicates attachment to thecyclopropane ring in endo configuration, and to the side chain in alphaor beta configuration).

A solution of the mixed Formula-VIII glycols (Formula XXXIX wherein Mand E are hydrogen) of Example 6 (2.38 g.) in 40 ml. of 100% formic acidis left standing 0.5 hr. at about 25° C. The mixture is thenconcentrated under reduced pressure. The residue is treated with asolution of phosphate buffer (pH 6.8) and about 10% sodium bicarbonateand extracted with dichloromethane. The dichloromethane solution isdried over sodium sulfate and concentrated under reduced pressure. Theresidue is separated by chromatography on silica gel, combining thosefractions shown by TLC to contain the title compound. Concentration ofthose fractions yields the title compound. R_(f) =0.2 in ethylacetate-Skellysolve B (40:60) on TLC plates.

EXAMPLE 23 PGF₂.sub.α and 15β-PGF₂.sub.α. Refer to Chart E.

A. Optically active tricyclic lactone acetal V -- A mixture of theFormula-IV acetal ketone isomer of Example 14-A (12.0 g.) and potassiumbicarbonate (6.1 g.) in 100 ml. of dichloromethane is treated withm-chloroperbenzoic acid (12.3 g. of 85%) in portions, with stirring andcooling to maintain the temperature below 30° C. After 2 hrs., 150 ml.of 5% sodium bicarbonate solution containing 9 g. of sodium thiosulfateis added. The dichloromethane layer is dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue isrecrystallized from ethyl acetate as the Formula-V tricyclic lactoneacetal wherein R₁ and R₂ taken together are --CH₂ --C(CH₃)₂ --CH₂ -- and˜ is endo; m.p. 127°-130° C., NMR peaks at 0.80, 1.29, 3.45, 3.72, 3.94(doublet), and 4.89 (multiplet) δ; infrared absorption peaks at 1765,1230, 1185, 1160, 1120, 1100, 1095, 1015, 1000, 980, 955, and 925 cm⁻ ¹; [α]_(D) ²⁵ + 9° (methanol).

B. Optically active tricyclic lactone aldehyde VI -- The acetal ketoneof Example 23-A above (4.43 g.) is dissolved in 60 ml. of 88% formicacid and held at about 50° C. for 1 hr. The solution is cooled anddiluted with 60 ml. of 1 N sodium hydroxide saturated with sodiumchloride, and then extracted with several portions of dichloromethane.The dichloromethane extracts are washed with 20 ml. of 10% sodiumcarbonate, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting oil is triturated with isopropyl etherand seeded to yield crystals of the corresponding Formula-VI tricycliclactone aldehyde, m.p. 62.5-64° C., NMR peaks at 2.48 (doublet), 2.82(doublet), 3.10 (multiplet), 5.12 (multiplet), and 9.84 (doublet);infrared absorption peaks at 1755, 1710, and 1695; [α]_(D) ²⁵ -30°(methanol).

C. Optically active tricyclic lactone heptene VII -- Following theprocedure of Example 5, the lactone aldehyde of Example 23-B above istransformed to the corresponding Formula-VII optically active lactoneheptene; NMR peaks at 0.6-3.0, 4.5-5.2, and 5.7 δ; infrared absorptionpeak at at 1700 cm⁻ ¹.

D. Bicyclic lactone diol X -- Following the procedures of Examples 19 to21, the tricyclic lactone heptene of Example 23-C above is transformedto the corresponding optically active Formula-X.sub.α and -X.sub.βlactone diols.

E. Title compounds -- Following the methods known in the art, the abovediols are transformed to the corresponding PGF₂.sub.α and 15β-PGF₂.sub.αproducts.

Following the procedures of steps C, D, and E above, the opticallyactive isomers of the Formula-VI aldehyde of Example 15 are transformedto PGF₂ -type products. Thus, PGF₂.sub.α and 15β-PGF₂.sub.α are obtainedfrom the isomer of Example 15-B; ent-PGF₂.sub.α and ent-15β-PGF₂.sub.αare obtained from the isomer of Example 15-A.

What is claimed is:
 1. A process for resolving a racemic mixture of anoxo compound of the formula ##SPC36##and of the mirror image thereof,wherein R₁ and R₂ are alkyl of one to 4 carbon atoms, inclusive, or,when taken together, ##EQU8## wherein R₃, R₄, R₅, R₆, and R₈ arehydrogen, alkyl of one to 4 carbon atoms, inclusive, or phenyl, with theproviso that not more than one of the R's is phenyl and the total numberof carbon atoms is from 2 to 10, inclusive; x is zero or one, and ˜indicates attachment of the moiety to the cyclopropane ring in exo orendo configuration, which comprises the steps of a. converting the oxocompound by reaction with an optically active ephedrine to a mixture ofoxazolidine diastereomers, b. separating at least one oxazolidinediastereomer from said mixture,c. hydrolyzing said oxazolidine to freethe optically active oxo compound, and d. recovering said opticallyactive oxo compound.
 2. A process of claim 1 wherein the oxo compound isan aldehyde of the formula ##SPC37##or of the mirror image thereof,wherein ˜ indicates attachment of the moiety to the cyclopropane ring inexo or endo configuration.
 3. A process of claim 1 wherein the oxocompound is an aldehyde of the formula ##SPC38##or the mirror imagethereof, wherein ˜ indicates attachment of the moiety to thecyclopropane ring in exo or endo configuration.
 4. A process of claim 1wherein the oxo compound is a ketone of the formula ##SPC39## or of themirror image thereof, wherein R₁, and R₂ are alkyl of one to 4 carbonatoms, inclusive, or, when taken together, ##EQU9## wherein R₃, R₄, R₅,R₆, and R₈ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, orphenyl, with the proviso that not more than one of the R's is phenyl andthe total number of carbon atoms is from 2 to 10, inclusive; s is zeroor one, and ˜ indicates attachment of the moiety to the cyclopropanering in exo or endo configuration.
 5. A process of claim 4 wherein R₁and R₂ taken together are --CH₂ --C(CH₃)₂ --CH₂ --.
 6. A process ofclaim 1 wherein the oxo compound is reacted with d-ephedrine.
 7. Aprocess of claim 1 wherein the oxo compound is reacted with 1-ephedrine.8. A process of claim 1 wherein the separating step is carried out byfractional crystallization from isopropyl ether.
 9. A process of claim 1wherein the separating step is carried out by fractional crystallizationfrom methanol.
 10. A process of claim 1 wherein the hydrolyzing step iscarried out with water and an acid catalyst.
 11. A process of claim 1wherein the hydrolyzing step is carried out with water in the presenceof silica gel.